Currently available therapy for advanced breast cancer is inadequate. Doxorubicin (DOX), one of the most effective anticancer drugs, is commonly used against breast cancer. However, its clinical use is restricted by dose-dependent toxicity (myelosuppression and cardiotoxicity), the emergence of multidrug resistance and its low specificity against cancer cells. PEGylated liposomal doxorubicin (Doxil(R)) is the first nanoformulations of DOX approved by FDA for the treatment of breast cancer. Although the encapsulation of DOX into liposome does result in decreased DOX-induced cardiomyopathy, its clinical anti-cancer efficacy is only marginally better than the parent drug. This could in part be explained by its relatively large size (ca. 130 nm), thus limiting the tumor tissue penetration and obviating the enhanced permeability retention (EPR) effect. It has been reported that smaller nanoparticles such as 30 nm micelles could penetrate poorly permeable tumors for a better anti-tumor effect. The smart DOX loaded micelles with smaller size (~20 nm) to be developed in this proposal may offer better efficacy and toxicity profile against breast cancer, therefore have great commercial potentials to lead to a marketable DOX-nanoformulation for the treatment of breast cancer patients. The overall goal of this Phase I SBIR proposal is to develop highly effective micelle formulation of DOX against breast cancer in preclinical animal models, providing validation regarding the feasibility for Phase II studies that will eventually lead to an IND filin to FDA. Our hypotheses are: (i) The smaller crosslinked micelle formulation of DOX, compared to Doxil(R) or its free form are more efficacious and less toxic against breast cancer; (ii) The addition of breast cancer targeting ligand(s) to the nanotherapeutics can facilitate the intracellular delivery of the nanocarriers to the tumor cells in vivo and therefore will greatly enhance their anti- tumor efficacies; and (iii) N-acetyl cysteine, when administered to the animal 24 hrs after the initial administration of the disulfide cross-linked nanoparticle drug, will furthr improve its therapeutic index. In this proposal, these three hypotheses will be tested in transgenic mouse mammary tumor model. The project addresses a critical issue in breast cancer research to reduce drug toxicity and increase drug efficacy. The proposed project takes advantage of the optimized high-affinity breast cancer targeting peptide ligands from the combinatorial library screening method and incorporates them into our newly developed crosslinked nanocarrier system against breast cancer. State of the art design of the nanocarriers via engineering telodendrimers with well-defined structures represents the frontier development of the nanomedicine, in terms of multiple functions, fine-tunable and highly reproducible structure and properties. The use of reversibly crosslinked targeting micelles to delivery DOX against breast cancer is highly innovative. It's an excellent approach to prevent pre-mature drug release during circulation and deliver high concentrations of drug to tumor site. It is expected that this research will lead to new approach for the treatment of breast cancer. Page 1